Parkinson's disease (PD) is a neurological disorder characterized neuropathologically as a loss of dopamine neurons of the substantia nigra. This neuronal loss manifests clinically as alterations in movement, such as Bradykinesia, rigidity and/or tremor (Gelb et al., Arch. Neurol., 56:33-39, (1999)). Human genetic data have identified genes linked to the development of PD. One of these genes was localized to chromosome 6 using a cohort of juvenile onset patients and identified as Parkin protein (Kitada et al., Nature, 392:605-608 (1998)). Parkin protein is an E3 ligase protein that functions in the ubiquitin-proteasome pathway (UPS) (Shimura, Nature Genetics, 25:302-305 (2000)). The UPS is a major cellular pathway involved in the targeted removal of proteins for degradation and E3 ligases function to identify and label substrates for degradation by cellular proteasomes (Hereshko et al., Ann. Rev. Biochem., 67:425-479 (1998)) or lysosomes (Hicke, Trends in Cell Biology, 9:107-112 (1999)).
Another hallmark of PD is the presence of insoluble proteinaceusus cellular inclusions known as Lewy Bodies. Lewy Bodies are comprised of many proteins, the most prominent being the α-synuclein protein (Spillantini et al., Nature, 388:839-40 (1997)). Point mutations in the α-synuclein gene or multiplications of the gene, result in PD (Polymeropoulos et al., Science, 276:2045-7 (1997); Kruger et al., Nature Genetics, 18:106-8 (1998)).
New therapeutic agents for treating Parkinson's disease are urgently needed. The present invention provides new methods and materials useful for identifying and validating such new therapeutic agents and for other uses.